July 2021 – Laboratory Genetics and Genomics Case 2

By MCL Education • July 9, 2021

A 23-year-old patient who has a son with Fragile X syndrome (FXS) is pregnant with another son. She requested genetic testing as soon as possible to determine if the current pregnancy is also affected with FXS. A chorionic villus sample was taken at 12.5 weeks gestation for FXS testing by repeat-primed PCR (see A for results). Follow-up methylation studies were performed, including methylation-sensitive digestion followed by repeat-primed PCR (see B for results).

Figure 1: FXS Testing

Given these results, what is the most appropriate next step? 

  • Report full mutation, but request follow-up methylation studies by amniocentesis at 15 weeks gestation
  • Report full mutation, consistent with a diagnosis of late-onset fragile X-associated tremor/ataxia syndrome (FXTAS)
  • Report full mutation, consistent with a diagnosis of FXS
  • Report as a negative result, as full mutation is not methylated 

The correct answer is ...

The correct answer is: report full mutation, but request follow-up methylation studies by amniocentesis at 15 weeks gestation.

Report full mutation, but request follow-up methylation studies by amniocentesis at 15 weeks gestation — Correct. At 12.5 weeks gestation, methylation and gene imprinting is not fully established. Thus, follow-up testing by amniocentesis at 15 weeks gestation is required to determine if the full mutation (>200 CGG repeats) is truly methylated (resulting in FMR1 silencing and FXS) or unmethylated (at risk for FXTAS)1. Note: It’s not uncommon to see extra peaks in patients with full mutations due to the instability of the allele; this could represent low-level size mosaicism. These could also just be artifact or signal bleed-through due to the nature and sensitivity of this assay.

References

  1. Monaghan, K., Lyon, E. & Spector, E. ACMG Standards and Guidelines for fragile X testing: a revision to the disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics and Genomics. Genet Med 15, 575–586 (2013). https://doi.org/10.1038/gim.2013.61
Photo of Laura Thompson, Ph.D.

Laura Thompson, Ph.D.

Resident, Laboratory Genetics and Genomics
Mayo Clinic

Linda Hasadsri, M.D., Ph.D.

Consultant, Laboratory Genetics and Genomics
Mayo Clinic

Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

MCL Education

This post was developed by our Education and Technical Publications Team.

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